A novel biophysical model on calcium and voltage dual dependent gating of calcium-activated chloride channel

Ca2+-activated Cl− channels (CaCCs) are anion-selective channels and involved in physiological processes such as electrolyte/fluid secretion, smooth muscle excitability, and olfactory perception which critically depend on the Ca2+ and voltage dual-dependent gating of channels. However, how the Ca2+ and voltage regulate the gating of CaCCs still unclear. In this work, the authors constructed a biophysical model to illustrate the dual-dependent gating of CaCCs. For validation, we applied our model on both native CaCCs and exogenous TMEM16A which is thought to be the molecular basis of CaCCs. Our data show that the native CaCCs may share universal gating mechanism. We confirmed the assumption that by binding with the channel, Ca2+ decreases the energy-barrier to open the channel, but not changes the voltage-sensitivity. For TMEM16A, our model indicates that the exogenous channels show different Ca2+ dependent gating mechanism from the native ones. These results advance the understanding of intracellular Ca2+ and membrane potential regulation in CaCCs, and shed new light on its function in aspect of physiology and pharmacology.